Introduction

Resveratrol has recently become popular as a component of topical cosmeceuticals for its anti-aging properties and other benefits. It has a wide range of effects on the skin, including antioxidant properties, chemopreventive properties, anti-inflammatory and antimicrobial properties, and treatment of skin scarring and hyperpigmentation, among others. All of these properties make resveratrol an ideal addition to topical anti-aging cosmeceuticals.

Background

Resveratrol (3,5,4′-trihydroxystilbene) is an antioxidant polyphenol of the stilbene family, naturally found in the skin and seeds of red grapes. It has been popularized as the key ingredient in red wine, which helps to protect cardiovascular health. Resveratrol is also naturally found in other plants, berries, peanuts, and roots, where it plays an antioxidant role and protects plants against stressors such as ultraviolet (UV) light and fungal infections.

As a major constituent of red wine, resveratrol was studied in great detail for its medical benefits after Drs. Renaud and Lorgerial noted a low incidence of heart disease in the French population whose diet is high in fat, the so-called “French paradox.” Epidemiological studies showed that high levels of red wine intake (20–30 g/day) were associated with a lower incidence of heart disease. Since then, interest in resveratrol skyrocketed and many studies have been performed to investigate its health benefits.

Aging is caused by many different factors such as the loss of deep bone structure and subcutaneous fat, in addition to oxidative skin damage caused by cumulative sun exposure. The oxidative theory has become one of the most well studied causes of aging, as antioxidants have become a popular component in dietary and topical cosmeceuticals.
Here, we discuss the unique anti-aging properties of resveratrol, its targets, and its use in topical cosmeceuticals.

Cosmeceutical Uses

Resveratrol and Skin Barrier Penetration

The ability of any topical cosmeceutical to permeate the skin barrier is essential to its ability to reach actively metabolic cells and affect their processes. With UV radiation and exposure to exogenous stressors, the antioxidants present in skin can be significantly depleted, leaving the skin vulnerable to oxidative damage. It is therefore imperative that cosmeceuticals be able to penetrate the skin barrier to effectively deliver their antioxidant benefits. An effective topical antioxidant should be able to permeate the stratum corneum and reach the deeper layers of skin including the remainder of the epidermis and dermis. There should not be significant systemic absorption of the antioxidant component.

An in vitro study by Abla and Banga3 investigated the permeation characteristics of resveratrol and other antioxidants. Resveratrol in a propylene glycol base was applied to porcine ear skin for 24 h and housed in a permeation unit (static Franz-type diffusion cells). Porcine skin was chosen for its high similarity to human skin. The polyphenols, which included resveratrol, catechin, and curcumin, showed a high concentration retained within the stratum corneum (90% retention) as compared with retinol, which permeated into the deeper layers of the skin (90% diffusion). Another similar in vitro mouse skin diffusion study by Hung et al.4 verified the retention of resveratrol within the stratum corneum. Moreover, in vivo permeation of mouse skin with topical resveratrol in various hydrogel bases for 12 h suggested the use of hydrogel to help retain resveratrol in the upper layers of skin.

A human skin diffusion study by Tfaili et al. investigated the cutaneous permeation of topical resveratrol and caffeine.5 A resveratrol solution (0.03 g/L) was applied to ex vivo human abdominal skin for 9 h. A permeation test was performed and Raman confocal microspectrometer was utilized to measure diffusion in real time. Both caffeine and resveratrol were found in higher concentrations in the superficial skin at 6 μM than at deeper layers.

These animal and human studies have shown resveratrol to be readily available in the stratum corneum, where the most exposure to reactive oxygen species (ROS) takes place, supporting the use of resveratrol in cosmeceuticals.

Antioxidant Properties

The skin is the largest organ in the body and is the outermost barrier. It is therefore frequently exposed to the oxidative stresses of everyday living, including UV radiation, air pollution, and toxins. This leads to the formation of ROS, hydrogen peroxide (H2O2), and free radicals, all of which can cause damage to DNA, RNA, lipids, and proteins within the skin. ROS is a well-known inducer of skin cancers, aging, and inflammation. Normal metabolic processes such as cytochrome P450 cycling and lipid peroxidation7 may also generate ROS, allowing free ROS to cause oxidative damage to cells within the body itself.

Skin has its own natural antioxidant system, which constantly neutralize ROS. This antioxidant system functions to chelate ROS or donate an electron to achieve stability. The skin’s antioxidant system contains several lipophilic and hydrophilic antioxidants including vitamin E, vitamin C, glutathione, ubiquinones, and carotenoids, among others. These antioxidants have been found throughout the skin. Several studies have shown that the amount of antioxidants present in the epidermis is greater than in the dermis, which is due to the fact that the outer layers of skin are most exposed to oxidative stressors.

Resveratrol is best known for its antioxidant properties. The cumulative oxidative damage caused by both UVA and UVB irradiation produces excess ROS. Additionally, oxidative processes such as glycation can cross-link glycosaminoglycans (GAGs) within the dermis, which can create the yellow-brown sallow complexion characteristic of photoaged skin.
To study the antioxidant capabilities of resveratrol against UVA, Chen et al.18 performed an in vitro study utilizing immortalized human keratinocyte cells (HaCaT cells). The HaCaT cells were subjected to UVA irradiation at a dose of 5 J/cm2 while incubated with either 0.01 mmol/L or 0.1 mmol/L of resveratrol. It was found that resveratrol was able to enhance cell proliferation, increase the activity of antioxidants superoxide dismutase (SOD) and glutathione peroxidase, decrease the amount of oxidative by-products such as maleic dialdehyde, and prevent injury to HaCaT cell ultrastructure in a dosedependent manner. There are other antioxidant properties of resveratrol. Resveratrol itself is able to directly scavenge free radicals such as hydroxyl, superoxide, and metal/enzymatic-induced and cellular generate radicals.19 It can also prevent lipid peroxidation through chelation of copper and works synergistically with other antioxidants such as alpha-tocopherol (vitamin E).20 Overall, resveratrol upregulates the expression of the transcription factor nuclear factor-E2-related factor-2 (Nrf2), which regulates several genes that help synthesize more antioxidants and remove ROS. These genes encode enzymes such as glutathione peroxidase, catalase, superoxide dismutase, and hemoxygenase-1. All of these properties support the use of resveratrol as a potent antioxidant.

Other Uses of Resveratrol

Resveratrol may be useful in other areas of medicine. It is known that resveratrol is naturally produced by several plants, including peanuts, mulberries, and skins of certain grapes, when under attack by bacterial or fungal pathogens. An in vitro study by O’Connor et al.55 showed that resveratrol significantly inhibited the growth of the gram-negative anaerobic bacteria A. actinomycetemcomitans and P. gingivalis, which are some of the causative bacteria in periodontal disease associated with tissue destruction. The bacteria were incubated with resveratrol (in DMSO, 0.052 g/mL) for 1, 3, 6, and 24 hours in an anaerobic chamber at 37°C. At each time interval, the cultures were plated on blood agar plates and colony growth was observed. Resveratrol significantly decreased viable counts at 1 hour of incubation, and continued being reduced in a time-dependent manner, and at 24 hours, no colonies were able to grow.
In a similar study, Nawrocki et  al. investigated the bactericidal effects of resveratrol against Haemophilus ducreyi, the Gram-negative bacterium responsible for the sexually transmitted disease chancroid. The minimum cidal concentration (MCC) of resveratrol was found to be 500 μg/mL, which caused a 99.99% decrease in viable bacteria. Resveratrol activity against Lactobacillus strains was also investigated to determine any negative effects on natural flora. The MCC of resveratrol at 500 μg/mL caused an insignificant decrease in Lactobacillus growth, even when co-cultured with H. ducreyi, demonstrating that resveratrol was safe to normal flora.

These studies suggested resveratrol as an effective antimicrobial.